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Vol. 27, Issue 1, 102-109, January 1999
Laboratory of Molecular Carcinogenesis (T.J.Y., K.W.K,
Y.S., H.V.G.) and
Laboratory of Metabolism (F.J.G.), National Cancer
Institute, National Institutes of Health, Bethesda, Maryland
Eight inhibitory monoclonal antibodies (MAbs) individually specific
to human cytochrome P-450 (P-450) 1A1, 1A2, 2A6, 2B6, 2C subfamily
(2C8, 2C9, 2C18 and 2C19), 2D6, 2E1, and 3A4/5 were used to define the
role of single P-450s in the metabolism of diazepam (DZ),
7-ethoxycoumarin (7-EC), and imipramine (IMI) in human liver microsomes
(HLM). The MAbs were added combinatorially to six HLM samples. With DZ
as a substrate, more than 80% of temazepam (TMZ) formation was
inhibited in all six samples by the addition of MAb to 3A4/5,
indicating an 80% contribution of 3A4/5 to TMZ formation. Nordiazepam
formation was inhibited with MAbs to 2B6 (6-23%), 2C subfamily
(12-61%) and 3A4/5 (14-45%). The MAbs to 1A1, 1A2, 2A6, 2D6, and
2E1 did not inhibit TMZ or nordiazepam formation; this indicates their
noninvolvement in DZ metabolism. The MAb-defined P-450 contribution to
7-EC Odeethylation in six HLM samples was 17 to
60% for 2E1, 15 to 46% for 2A6, and 5 to 22% for 1A2, reflecting the
role and variation of each P-450 in this activity. MAbs to 1A1, the 2C
subfamily, 2D6, and 3A4/5 did not affect 7-EC metabolism in the HLM
samples. IMI is metabolized mainly to 2-hydroxyimipramine by expressed
2C19 and 2D6, and desipramine (DIM) by expressed 1A2, 2C18, 2C19 and
2D6. Expressed 1A1, 2C9, and 3A4 showed low activities for the
formation of DIM. Of six HLM samples, five showed IMI hydroxylation
activity (0.35-2.6 nmol/min/nmol P-450) while one (HL43) lacked
hydroxylation activity. All six HLM samples showed
Ndeethylation activity (0.74-1.4 nmol/min/nmol P-450). The MAb-determined contribution of 2D6 and 2C19 to
2-hydroxyimipramine formation ranged from 47 to 90% and from 0 to
49%, respectively, while HL43 did not show 2-hydroxylation. The role
of P-450s involved in DIM formation varied for 2C19 (13-50%), 1A2
(23-41%), and 3A4 (8-26%). These studies demonstrate a system for
identifying the quantitative metabolic role of single P-450s and their
interindividual variability in a tissue containing multiple P-450s. The
system using inhibitory MAbs is simple, precise, and applicable to any P-450-mediated catalytic activity including that for drugs,
carcinogens, mutagens, toxic chemicals and endobiotics.
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